(4R-Cis)-1,1 dimethylethyl 6-(2-aminoethyl)-2,2-dimethyl-1,3-dioxan-4-acetate is a key intermediate in the preparation of (2R-trans)-5-(4-fluorophenyl)-2-(1-methylethyl)-N,4-diphenyl]-1-[2-(tetrah ydro-4-hydroxy -6-oxo-2H-pyran-2-yl)ethyl]-1H-pyrrole-3-carboxamide or the salt of the hydroxy acid, [R-(R*,R*)]-2-(4-fluorophenyl)-.beta.,.delta.-dihydroxy-5-(1-methylethyl)- 3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid calcium salt (2:1), corresponding to the opened lactone ring of the aforementioned compound described in U.S. Pat. Nos. 4,647,576 and 4,681,893, which are herein incorporated by reference. The aforementioned compound is useful as an inhibitor of the enzyme 3-hydroxy-3-methylglutaryl-Coenzyme A reductase (HMG-CoA reductase) and is thus useful as a hypolipidemic and hypocholesterolemic agent.
(4R-Cis)-1,1-dimethylethyl 6-(2-aminoethyl)-2,2-dimethyl-1,3-dioxane-4-acetate may be, in turn, prepared from (4R-Cis)-1,1-dimethylethyl 6-cyanomethyl-2,2-dimethyl-1,3-dioxane-4-acetate which may, in turn, be prepared from (5R)-1,1-dimethylethyl 6-cyano-5-hydroxy-3-oxo-hexanoate.
A synthetic procedure for preparing (5R)-1,1-dimethylethyl 6-cyano-5-hydroxy-3-oxo-hexanoate is disclosed in U.S. Pat. No. 5,003,080. The aforementioned procedure involves a linear synthetic route involving 5 steps, involving use of protected intermediates. Although this procedure provides the target compound it is difficult to conduct on large scale, requires use of expensive starting materials, and involves the use of costly protecting group and deprotecting group reagents in the process.
There are several literature reports in which the anion of tertiary butyl acetate is reacted with a 3-hydroxy ester in the desired manner to afford a .beta.-keto-.delta. ester, for example, Lynch, J. E., et al, Tetrahedron Letters, Volume 23, pages 1385-1388 (1987) and U.S. Pat. No. 4,970,313. However, none of the known examples contain a nitrile group. Moreover, U.S. Pat. No. 4,983,759 discloses the reaction of a nitrile with the anion of tertiary butyl acetate resulting in reaction at the nitrile end of the molecule.
Thus, we have surprisingly and unexpectedly found that the reaction of the anion of tertiary butyl acetate with (3R)-4-cyano-3-hydroxybutyric acid esters proceeds very efficiently to afford the desired compound, (5R)-1,1-dimethylethyl 6-cyano-5-hydroxy-3-oxo-hexanoate.
The object of the present invention is an improved, short, efficient, and economical process for the preparation of (5R)-1,1-dimethylethyl 6-cyano-5-hydroxy-3-oxo-hexanoate. Thus, the present method avoids costly starting materials, protection and deprotection of intermediates of the prior method and is amenable to large scale synthesis.